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WO2004101512A2 - Inihbiteurs de l'integrase de la naphtyridine - Google Patents

Inihbiteurs de l'integrase de la naphtyridine Download PDF

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Publication number
WO2004101512A2
WO2004101512A2 PCT/US2004/014814 US2004014814W WO2004101512A2 WO 2004101512 A2 WO2004101512 A2 WO 2004101512A2 US 2004014814 W US2004014814 W US 2004014814W WO 2004101512 A2 WO2004101512 A2 WO 2004101512A2
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WO
WIPO (PCT)
Prior art keywords
naphthyridin
fluorobenzyl
hydroxy
oxadiazol
heterocycle
Prior art date
Application number
PCT/US2004/014814
Other languages
English (en)
Other versions
WO2004101512A3 (fr
Inventor
Brian A. Johns
Original Assignee
Smithkline Beecham Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Smithkline Beecham Corporation filed Critical Smithkline Beecham Corporation
Priority to US10/556,311 priority Critical patent/US7812016B2/en
Priority to EP04751959A priority patent/EP1622615A4/fr
Priority to JP2006532973A priority patent/JP2006528694A/ja
Publication of WO2004101512A2 publication Critical patent/WO2004101512A2/fr
Publication of WO2004101512A3 publication Critical patent/WO2004101512A3/fr
Priority to US12/871,230 priority patent/US20110003794A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents

Definitions

  • NAPHTHYBIDINE INTEGRASE INHIBITORS
  • HIV human immunodeficiency virus
  • AIDS acquired immunodeficiency syndrome
  • ARC AIDS-related complex
  • HIV is a retrovirus; the conversion of its RNA to DNA is accomplished through the action of the enzyme reverse transcriptase.
  • Compounds that inhibit the function of reverse transcriptase inhibit replication of HIV in infected cells. Such compounds are useful in the prevention or treatment of HIV infection in humans.
  • a required step in HIV replication in human T-cells is the insertion by virally- encoded integrase of proviral DNA into the host cell genome. Integration is believed to be mediated by integrase in a process involving assembly of a stable nucleoprotein complex with viral DNA sequences, cleavage of two nucleotides from the 3' termini of the linear proviral DNA and covalent joining of the recessed 3' OH termini of the proviral DNA at a staggered cut made at the host target site. The repair synthesis of the resultant gap may be accomplished by cellular enzymes.
  • HIV integrase is an attractive target for the discovery of new therapeutics due to its important role in viral infections, particularly HIV infections.
  • Integrase inhibitors are disclosed in WO02/70486.
  • the compounds of the present invention exhibit advantages over previously disclosed integrase inhibitors, for example increased potency, metabolic stability, increased therapeutic index, or other pharmaceutical properties.
  • the present invention features compounds that are HIV integrase inhibitors and therefore are useful in the inhibition of HIV replication, the prevention and/or treatment of infection by HIV, and in the treatment of AIDS and/or ARC. Accordingly, the present invention features compounds of formula (I):
  • R 1 is hydrogen, halogen, C 1-8 alkyl, C 3- 6cycloalkyl, C ⁇ -8 haloalkyl, C6- ⁇ 4 aralkyl, C 2- ealkenyl, C 3-6 cycloalkenyl, C 3-6 alkynyl, C ⁇ -8 alkoxy, -CN, -R 3 OR 4 , -R 3 C(0)R 4 , - C(0)R 4 , -R 3 C(0)OR 4 , -R 3 COR 4 , -C(0)OR 4 , -R 3 SR 4 , -SR 4 , -SR 4 , -SR 4 , -SR 4 , -SR 4 , -SR 4 , -SR 4 , -SR 4 , -SR 4 , -SR 4 , -SR 4 , -SR 4 , -SR 4 , -SR 4 , -SR 4 , -SR 4 , -SR 4 , -
  • R 2 is C 3- 6cycloalkyl, C 6-14 aryl optionally substituted with one or more substituents independently selected from the group consisting of hydrogen, halogen, hydroxy, C ⁇ . 8 alkyl, -OR 5 , and NR 5 R 6 , or heterocycle optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, C ⁇ -8 alkyl, -OR 5 , andNR 5 R 6 ;
  • R 3 is C 1-8 alkyl, C 3-6 cycloalkyl, haloC 1-8 alkyl, C 2-6 alkenyl, C 3-6 cycloalkenyl, or C 3 . 6 alkenyl, or heterocycle;
  • R 4 is hydrogen, C 1-8 alkyl, C 3-6 cycloalkyl, C ⁇ -8 haloalkyl, C 6-14 aryl, C 6 - ⁇ 4 aralkyl, C 2- 6 alkenyl, or C 3-6 cycloalkenyl, C 3-6 alkynyl, or heterocycle;
  • R 5 and R 6 are independently selected from the group consisting of hydrogen, C ⁇ _ shaloalkyl, C 1-8 alkylC 3-6 cycloalkyl, C 6- ⁇ 4 aryl, C 6-1 aralkyl, -C(0) m R 7 , -C(0)C(0) m R 7 , -C(O) m heterocycle, -C(0)C(0) m heterocycle, -S(O) n heterocycle, -heterocycle, and Y optionally substituted with one or more -OR 7 , -C(O) m R 7 , -S(0) n R 7 , -S(O) n R 7 , -C(O) m heterocycle, -S(0) n heterocycle, -C(0)C(0) m R 7 , -C(0)C(0) m heterocycle, - heterocycle, -Oheterocycle;
  • R 7 is hydrogen, C 1-8 alkyl, C 3-6 cycloalkyl, -Ycycloalkyl, -YOH, -Y(OY) w where w is 1-10;
  • A is heterocycle
  • Q is C ⁇ -3 alkyl, -NR 4 , -0-, -C(O), -C(OR , S(0) 2 , or -CF 2 ;
  • the present invention includes the compounds of Formula (I) above, useful in treating or preventing viral infections, particularly HIV infections, pharmaceutical compositions comprising compounds of Formula (I), and processes for preparing the compounds.
  • the present invention also features a compound of Formula (I) wherein R 1 is hydrogen, halogen, C 1-8 alkyl, C 3-6 cycloalkyl, C 1-8 haloalkyl, C 6- ⁇ 4 aralkyl, C 2-6 alkenyl,
  • the present invention features a compound of Formula (I) wherein R 1 is C 6- 14 aryl optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C 1-8 alkyl, C ⁇ -8 haloalkyl, -OR 3 , -SR 3 , - CN, hydroxy, -R 3 C(0)N(R 4 ) 2 , -C(0)N(R 4 ) 2 , -R 3 C(0)R 4 , -R 3 OR 3 OH, -C(0)R 4 , - N(R 4 )C(0)R 4 , -N(R 4 )C(0)R 4 ; and all other substituents are as defined above, or a pharmaceutically acceptable derivative thereof.
  • the present invention features a compound of Formula (I) wherein R 1 is - N(R 4 ) 2 , -NC(0)N(R 4 ) 2> -N(R 4 )C(0)R 4 , -N(R )C(0)OR 4 , -N(R 4 )C(0)C(0)N(R 4 ) 2 , - N(R 4 )C(R 4 )(0), -N(R 4 )C(R 4 )(0-NS(0) 2 NR 4 -N(R )S(0) 2 R 4 , -N(R 4 )R 3 SR 4 , -
  • the present invention features a compound of Formula (I) wherein R 1 is -C(0)R 4 , - C(0)OR 4 , -C(0)N(R 4 ) 2; and all other substituents are as defined above, or a pharmaceutically acceptable derivative thereof.
  • the present invention features a compound of Formula (I) wherein R 1 is Y optionally substituted with one or more substituents independently selected from the group consisting of -OR 5 , -NR 5 R 6 , -N(R 5 )YNR 6 , -C(0) m R 5 , -C(0)NR 5 R 6 , -N(R 5 )C(0) m R 5 , -N(R 5 )Y p C(0)NR 5 R 6 , -N(R 5 )Y p C(0) mheterocycle, -0(Y)C(0)NR 5 R 6 , - S(0) n YpC(0)NR 5 R 6 , -S(0) consentR 5 R 6 , -S(0) n NR 5 , -S(O) nheterocycle, -N(R 5 )Y p S(0) n NR 5 R 6 , -C(O) mheterocycle, -S(O) nheterocycle,
  • the present invention features a compound of Formula (I) wherein R 1 is C 6- ⁇ 4 aryl optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C 1-8 alkyl, C ⁇ -8 haloalkyl, -OR 3 , -SR 3 , - CN, hydroxy, -R 3 C(O)N(R 4 ) 2 , -C(0)N(R 4 ) 2 , -R 3 C(O)R 4 , -R 3 OR 3 OH, -C(O)R 4 , - N(R 4 )C(0)R 4 , -N(R 4 )C(0)R 4 ;
  • A is oxadiazolyl, triazolyl, thiadazolyl, oxazolyl;
  • R 2 is C 6 - ⁇ 4 aryl optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, hydroxy, C ⁇
  • the present invention features a compound of Formula (I) wherein R 1 is - N(R 4 ) 2 , -NC(0)N(R 4 ) 2) -N(R 4 )C(0)R 4 , -N(R 4 )C(0)OR 4 , -N(R 4 )C(0)C(0)N(R 4 ) 2 , - N(R 4 )C(R 4 )(0), -N(R 4 )C(R 4 )(0-NS(0) 2 NR 4 , -N(R 4 )S(0) 2 R 4 , -N(R 4 )R 3 SR 4 , -
  • A is oxadiazolyl, triazolyl, thiadazolyl, oxazolyl;
  • R 2 is C6 -14 aryl optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, hydroxy, Ci. 8 alkyl, -OR 5 , andNR 5 R 6 ;
  • Q is C ⁇ -3 alkyl; or a pharmaceutically acceptable derivative thereof.
  • the present invention features a compound of Formula (I) wherein R 1 is - C(0)R 4 , -C(0)OR 4 , -C(0)N(R 4 ) 2; A is oxadiazolyl, triazolyl, thiadazolyl, oxazolyl; R 2 is C 6-14 aryl optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, hydroxy, .salkyl, -OR 5 , andNR 5 R 6 ; Q is . 3 alkyl; or pharmaceutically acceptable derivative thereof.
  • the present invention features a compound of Formula (I) wherein R 1 is Y optionally substituted with one or more substituents independently selected from the group consisting of -OR 5 , -NR 5 R 6 , -N(R 5 )YNR 6 , -C(0) ra R 5 , -C(0)NR 5 R 6 , -N(R 5 )C(0) m R 5 , -N(R 5 )Y p C(0)NR 5 R 6 , -N(R 5 )Y p C(0) m heterocycle, -0(Y)C(0)NR 5 R 6 , - S(O) deliberatelyY p C(O)NR 5 R 6 , -S(0) n R 5 R 6 , -S(0) n NR 5 , -S(O) nheterocycle, -N(R 5 )Y p S(O) n NR 5 R 6 , -C(O) mheterocycle, -S(O) n
  • the present invention also features a compound of formula (I) wherein R 1 is selected from heterocycle optionally substituted with one or more substituents independently selected from group consisting of halogen, hydroxy, C 1-8 alkyl, Ci. shaloalkyl, -OR 3 , -SR 3 , -CN, hydroxy, oxo, -R 3 C(0)N(R 4 ) 2 , -C(0)N(R 4 ) 2 , -R 3 C(0)R 4 , -R 3 OR 3 OH, -C(0)R 4 , -N(R 4 )C(0)R 4 , -N(R 4 )C(0)R 4 , -R 3 N(R 4 )C(0)R 4 , -N(R ) 2 , - R 3 N(R 4 ) 2> C 6-14 aryl, C 6 - ⁇ 4 aryloxy, heterocycle, and R 3 optionally substituted with C 6- ⁇ 4 aryl;
  • A is ox
  • alkyl refers to a straight-chain or branched-chain saturated aliphatic hydrocarbon radical containing the specified number of carbon atoms.
  • alkyl radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, n-hexyl and the like.
  • cycloalkyl refers to a saturated or partially saturated carbocyclic ring composed of 3-6 carbons in any chemically stable configuration.
  • suitable carbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclohexenyl.
  • alkenyl refers to a straight-chain or branched-chain alkyl group with at least one carbon-carbon double bond.
  • alkenyl radicals include, but are not limited to, ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, hexenyl, hexadienyl and the like.
  • alkynyl refers to hydrocarbon groups of either a straight or branched configuration with one or more carbon-carbon triple bonds which may occur in any stable point along the chain, such as ethynyl, propynyl, butynyl, pentynyl, and the like.
  • alkoxy refers to an alkyl ether radical, wherein the term “alkyl” is defined above.
  • suitable alkyl ether radicals include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert- butoxy and the like.
  • alkylene chain refers to a straight or branched hydrocarbon chain that may be fully saturated or have one or more units of unsaturation. The unsaturation may occur in any stable point along the chain. The double bond(s) in the unsaturated alkylene chain may be in either the cis or trans configuration.
  • halogen refers fluorine (F), chlorine (Cl), bromine (Br), or iodine
  • aryl alone or in combination with any other term, refers to a carbocyclic aromatic moiety (such as phenyl or naphthyl) containing the specified number of carbon atoms, preferably from 6-14 carbon atoms, and more preferably from 6-10 carbon atoms.
  • aryl radicals include, but are not limited to, phenyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl, indanyl, phenanthridinyl and the like.
  • aryl also includes each possible positional isomer of an aromatic hydrocarbon radical, such as in 1 -naphthyl, 2-naphthyl, 5-tetrahydronaphthyl, 6- tetrahydronaphthyl, 1 -phenanthridinyl, 2-phenanthridinyl, 3 -phenanthridinyl, 4- phenanthridinyl, 7-phenanthridinyl, 8-phenanthridinyl, 9-phenanthridinyl and 10- phenanthridinyl.
  • aryl radicals include, but are not limited to, phenyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl, indanyl, phenanthridinyl and the like.
  • aralkyl refers to an alkyl group substituted by an aryl. Examples of aralkyl groups include, but are not limited to, benzyl and phenethyl.
  • heterocycle refers to a 3- to 7- membered monocyclic heterocyclic ring or 8-to 11- membered bicyclic heterocyclic ring system any ring of which is either saturated, partially saturated or unsaturated, and which may be optionally benzofused if monocyclic.
  • Each heterocycle consists of one or more carbon atoms and from one to four heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen atom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the heterocyclic ring may be attached at any carbon or heteroatom, provided that the attachment results in the creation of a stable structure.
  • Preferred heterocycles include 5-7 membered monocyclic heterocycles and 8-10 membered bicyclic heterocycles.
  • Heteroaromatics or “heteroaryl” are included within the heterocycles as defined above and generally refers to a heterocycle in which the ring system is an aromatic monocyclic or polycyclic ring radical containing five to twenty carbon atoms, preferably five to ten carbon atoms, in which one or more ring carbons, preferably one to four, are each replaced by a heteroatom such as N, O, S and P.
  • heteroaryl groups include 5-6 membered monocyclic heteroaryls and 8 - 10 membered bicyclic heteroaryls.
  • heterocycle “heterocyclic” or “heterocyclyl” is a group in which a nonaromatic heteroatom-containing ring is fused to one or more aromatic rings, such as in an indolinyl, chromanyl, phenanthridinyl or tetrahydro-quinolinyl, where the radical or point of attachment is on the non-aromatic heteroatom-containing ring.
  • heterocycle, “heterocyclic” or “heterocyclyl” also included each possible positional isomer of a heterocyclic radical, such as in 1- indolinyl, 2-indolinyl, 3-indolinyl.
  • heterocycles include imidazolyl, imidazolinoyl, imidazolidinyl, quinolyl, isoquinolyl, indolyl, indazolyl, indazolinolyl, perhydropyridazyl, pyridazyl, pyridyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazinyl, quinoxolyl, piperidinyl, pyranyl, pyrazolinyl, piperazinyl, pyrimidinyl, pyridazinyl, mo ⁇ holinyl, thiamo ⁇ holinyl, furyl, thienyl, triazolyl, thiazolyl, carbolinyl, tetrazolyl, thiazolidinyl, benzofuranoyl, thiamo ⁇ holinyl sulfone, oxazolyl,
  • heteroatom means nitrogen, oxygen, or sulfur and includes any oxidized form of nitrogen, such as N(O) ⁇ N ⁇ -O " ⁇ and sulfur such as S(O) and S(0) 2 , and the quaternized form of any basic nitrogen.
  • a combination of substituents or variables is permissible only if such a combination results in a stable or chemically feasible compound.
  • a stable compound or chemically feasible compound is one in which the chemical structure is not substantially altered when kept at a temperature of 40 °C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
  • structures depicted herein are also meant to include all stereochemical forms of the structure, i.e., the R and S configurations for each asymmetric center. Therefore, racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereoisomers of the present compounds are expressly included within the scope of the invention. Although the specific compounds exemplified herein may be depicted in a particular stereochemical configuration, compounds having either the opposite stereochemistry at any given chiral center or mixtures thereof are also envisioned.
  • structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are also within the scope of this invention.
  • pharmaceutically effective amount refers to an amount effective in treating a virus infection, for example an HIV infection, in a patient either as monotherapy or in combination with other agents.
  • treating refers to the alleviation of symptoms of a particular disorder in a patient, or the improvement of an ascertainable measurement associated with a particular disorder, and may include the suppression of symptom recurrence in an asymptomatic patient such as a patient in whom a viral infection has become latent.
  • prolactically effective amount refers to an amount effective in preventing a virus infection, for example an HIV infection, or preventing the occurrence of symptoms of such an infection, in a patient.
  • patient refers to a mammal, including a human.
  • pharmaceutically acceptable carrier or adjuvant refers to a carrier or adjuvant that may be administered to a patient, together with a compound of this invention, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the antiviral agent.
  • treatment refers to the alleviation of symptoms of a particular disorder in a patient, or the improvement of an ascertainable measurement associated with a particular disorder, and may include the suppression of symptom recurrence in an asymptomatic patient such as a patient in whom a viral infection has become latent.
  • prophylaxis refers to preventing a disease or condition or preventing the occurrence of symptoms of such a disease or condition, in a patient.
  • patient refers to a mammal, including a human.
  • the term "subject” refers to a patient, animal or a biological sample.
  • biological sample includes, without limitation, cell cultures or extracts thereof; preparations of an enzyme suitable for in vitro assay; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.
  • the compounds according to the invention are defined to include pharmaceutically acceptable derivatives thereof.
  • a "pharmaceutically acceptable derivative” means any pharmaceutically acceptable salt, ester, salt of an ester, ether, or other derivative of a compound of this invention which, upon administration to a recipient, is capable of providing directly or indirectly a compound of this invention or an inhibitorily active metabolite or residue thereof.
  • Particularly favored derivatives and prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a mammal, for example, by allowing an orally administered compound to be more readily absorbed into the blood, or which enhance delivery of the parent compound to a biological compartment, for example, the brain or lymphatic system, relative to the parent species.
  • Pharmaceutically acceptable salts of the compounds according to the invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases.
  • suitable acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycollic, lactic, salicyclic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic and benzenesulfonic acids.
  • Salts derived from appropriate bases include alkali metal (e.g. sodium), alkaline earth metal (e.g., magnesium), ammonium, NW 4 + (wherein W is C 1-4 alkyl) and other amine salts.
  • Physiologically acceptable salts of a hydrogen atom or an amino group include salts or organic carboxylic acids such as acetic, lactic, tartaric, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids and inorganic acids such as hydrochloric, sulfuric, phosphoric and sulfamic acids.
  • organic carboxylic acids such as acetic, lactic, tartaric, malic, isethionic, lactobionic and succinic acids
  • organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids
  • inorganic acids such as hydrochloric, sulfuric, phosphoric and sulfamic acids.
  • Physiologically acceptable salts of a compound with a hydroxy group include the anion of said compound in combination with a suitable cation such as Na + , NH 4 + , and NW 4 + (wherein W is a C 1-4 alkyl group).
  • Preferred salts include sodium, calcium, potassium, choline, meglumine, and quaternary ammonium.
  • Any reference to any of the above compounds also includes a reference to a pharmaceutically acceptable salt thereof.
  • Salts of the compounds of the present invention may be made by methods known to a person skilled in the art. For example, treatment of a compound of the present invention with an appropriate base or acid in an appropriate solvent will yield the corresponding salt.
  • Esters of the compounds of the present invention are independently selected from the following groups: (1) carboxylic acid esters obtained by esterification of the hydroxy groups, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, acetyl, n-propyl, t-butyl, or n-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted by, for example, halogen, C 1-4 alkyl, or C ⁇ _ 4 alkoxy or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters (for example, L-valyl or L-isoleucyl
  • any alkyl moiety present advantageously contains from 1 to 18 carbon atoms, particularly from 1 to 6 carbon atoms, more particularly from 1 to 4 carbon atoms, Any cycloalkyl moiety present in such esters advantageously contains from 3 to 6 carbon atoms. Any aryl moiety present in such esters advantageously comprises a phenyl group.
  • Ethers of the compounds of the present invention include, but are not limited to methyl, ethyl, butyl and the like.
  • the present invention features a compound selected from the group consisting of: 7-(5-benzyl-4H-l,2,4-triazol-3-yl)-l,6-naphthyridin-8-ol;
  • One aspect of the instant invention relates to methods of treating or preventing viral infection, for example an HIV infection, in a biological sample comprising contacting the biological sample with compounds of formula I or pharmaceutically acceptable derivatives thereof.
  • Another aspect of the instant invention relates to methods of treating or preventing viral infection, for example, an HIV infection, in a patient comprising administering to the patient a therapeutically effective amount of compounds of formula I or pharmaceutically acceptable derivatives thereof.
  • the compounds according to the invention are particularly suited to the treatment or prophylaxis of HIV infections and associated conditions. Reference herein to treatment extends to prophylaxis as well as the treatment of established infections, symptoms, and associated clinical conditions such as AIDS related complex (ARC), Kaposi's sarcoma, and AIDS dementia.
  • ARC AIDS related complex
  • Kaposi's sarcoma Kaposi's sarcoma
  • AIDS dementia AIDS related complex
  • compositions may be formulated into compositions.
  • the composition is a pharmaceutical composition, which comprises a compound of formula I and pharmaceutically acceptable carrier, adjuvant or vehicle.
  • the composition comprises an amount of a compound of the present invention effective to treat or prevent viral infection, for example an HIV infection, in a biological sample or in a patient.
  • compounds of this invention and pharmaceutical compositions thereof which comprise an amount of a compound of the present innovation effective to inhibit viral replication or to treat or prevent a viral infection or disease or disorder, for example an HIV infection, and a pharmaceutically acceptable carrier, adjuvant or vehicle, may be formulated for administration to a patient, for example, for oral administration.
  • the present invention features compounds according to the invention for use in medical therapy, for example for the treatment or prophylaxis of a viral infection, for example an HIV infection and associated conditions.
  • the compounds according to the invention are especially useful for the treatment of AIDS and related clinical conditions such as AIDS related complex (ARC), progressive generalized lymphadenopathy (PGL), Kaposi's sarcoma, thromobocytopenic pu ⁇ ura, AIDS- related neurological conditions such as AIDS dementia complex, multiple sclerosis or tropical paraperesis, anti-HIV antibody-positive and HIV-positive conditions, including such conditions in asymptomatic patients.
  • the present invention provides a method for the treatment or prevention of the symptoms or effects of a viral infection in an infected patient, for example, a mammal including a human, which comprises administering to said patient a pharmaceutically effective amount of a compound according to the invention.
  • the viral infection is a retroviral infection, in particular an HIV infection.
  • the present invention further includes the use of a compound according to the invention in the manufacture of a medicament for administration to a subject for the treatment of a viral infection, in particular and HIV infection.
  • the compounds according to the invention may also be used in adjuvant therapy in the treatment of HIV infections or HIV-associated symptoms or effects, for example Kaposi's sarcoma.
  • the present invention further provides a method for the treatment of a clinical condition in a patient, for example, a mammal including a human which clinical condition includes those which have been discussed hereinbefore, which comprises treating said patient with a pharmaceutically effective amount of a compound according to the invention.
  • the present invention also includes a method for the treatment or prophylaxis of any of the aforementioned diseases or conditions.
  • Reference herein to treatment extends to prophylaxis as well as the treatment of established conditions, disorders and infections, symptoms thereof, and associated.
  • the above compounds according to the invention and their pharmaceutically acceptable derivatives may be employed in combination with other therapeutic agents for the treatment of the above infections or conditions.
  • Combination therapies according to the present invention comprise the administration of a compound of the present invention or a pharmaceutically acceptable derivative thereof and another pharmaceutically active agent.
  • the active ingredient(s) and pharmaceutically active agents may be administered simultaneously (i.e., concurrently) in either the same or different pharmaceutical compositions or sequentially in any order.
  • the amounts of the active ingredient(s) and pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • Such therapeutic agents include, but are not limited to, agents that are effective for the treatment of viral infections or associated conditions.
  • agents that are effective for the treatment of viral infections or associated conditions.
  • these agents are (1-alpha, 2-beta, 3-alpha)-9-[2,3- bis(hydroxymethyl)cyclobutyl]guanine [(-)BHCG, SQ-34514, lobucavir]; 9- [(2R,3R,4S)-3,4-bis(hydroxy methyl)2-oxetanosyl]adenme (oxetanocin-G); acyclic nucleosides, for example acyclovir, valaciclovir, famciclovir, ganciclovir, and penciclovir; acyclic nucleoside phosphonates, for example (S)-l-(3-hydroxy-2- phosphonyl-methoxypropyl) cytosine (HPMPC), [[[2-(6-amino-9H-pur
  • ribonucleotide reductase inhibitors for example 2-acetylpyridine 5-[(2-chloroanilino)thiocarbonyl) thiocarbonohydrazone and hydroxyurea
  • nucleoside reverse transcriptase inhibitors for example 3'-azido-3'-deoxythymidine (AZT, zidovudine), 2',3'-dideoxycytidine (ddC, zalcitabine), 2',3'-dideoxyadenosine, 2',3'-dideoxyinosine (ddl, didanosine), 2',3'-didehydrothymidine (d4T, stavudine), (-)-beta-D-2,6-diaminopurine dioxolane (DAPD), 3'-azido-2',3'-dideoxythymidine-5
  • the present invention further includes the use of a compound according to the invention in the manufacture of a medicament for simultaneous or sequential administration with at least another therapeutic agent, such as those defined hereinbefore.
  • Compounds of the present invention may be administered with an agent known to inhibit or reduce the metabolism of compounds, for example ritonavir. Accordingly, the present invention features a method for the treatment or prophylaxis of a disease as hereinbefore described by administration of a compound of the present invention in combination with a metabolic inhibitor. Such combination may be administered simultaneously or sequentially.
  • a suitable dose for each of the above-mentioned conditions will be in the range of 0.01 to 250 mg per kilogram body weight of the recipient (e.g. a human) per day, preferably in the range of 0.1 to 100 mg per kilogram body weight per day and most preferably in the range 0.5 to 30 mg per kilogram body weight per day and particularly in the range 1.0 to 20 mg per kilogram body weight per day.
  • all weights of active ingredient are calculated as the parent compound of formula (I); for salts or esters thereof, the weights would be increased proportionally.
  • the desired dose may be presented as one, two, three, four, five, six or more sub-doses administered at appropriate intervals throughout the day. In some cases the desired dose may be given on alternative days. These sub-doses may be administered in unit dosage forms, for example, containing 10 to 1000 mg or 50 to 500 mg, preferably 20 to 500 mg, and most preferably 50 to 400 mg of active ingredient per unit dosage form.
  • compositions of the present invention comprise at least one active ingredient, as defined above, together with one or more acceptable carriers thereof and optionally other therapeutic agents.
  • Each carrier must be acceptable in the sense of being compatible with the other ingredients of the composition and not injurious to the patient.
  • compositions include those suitable for oral, rectal, nasal, topical (including transdermal, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, and intravitreal) administration.
  • the compositions may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Such methods represent a further feature of the present invention and include the step of bringing into association the active ingredients with the carrier, which constitutes one or more accessory ingredients.
  • the compositions are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.
  • the present invention further includes a pharmaceutical composition as hereinbefore defined wherein a compound of the present invention or a pharmaceutically acceptable derivative thereof and another therapeutic agent are presented separately from one another as a kit of parts.
  • Compositions suitable for transdermal administration may be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Such patches suitably contain the active compound 1) in an optionally buffered, aqueous solution or 2) dissolved and or dispersed in an adhesive or 3) dispersed in a polymer.
  • a suitable concentration of the active compound is about 1% to 25%), preferably about 3% to 15%>.
  • the active compound may be delivered from the patch by electrotransport or iontophoresis as generally described in Pharmaceutical Research 3(6), 318 (1986).
  • compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, caplets, cachets or tablets each containing a predetermined amount of the active ingredients; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredients in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g. povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g. sodium starch glycollate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose) surface-active or dispersing agent.
  • Molded tablets may be made by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredients therein using, for example, hyckoxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.
  • Pharmaceutical compositions suitable for topical administration in the mouth include lozenges comprising the active ingredients in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray. Pharmaceutical compositions may contain in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • Pharmaceutical compositions for rectal administration may be presented as a suppository with a suitable carrier comprising, for example, cocoa butter or a salicylate or other materials commonly used in the art. The suppositories may be conveniently formed by admixture of the active combination with the softened or melted carrier(s) followed by chilling and shaping in molds.
  • compositions suitable for parenteral administration include aqueous and nonaqueous isotonic sterile injection solutions which may contain anti- oxidants, buffers, bacteriostats and solutes which render the pharmaceutical composition isotonic with the blood of the intended recipient; and aqueous and non- aqueous sterile suspensions which may include suspending agents and thickening agents; and liposomes or other microparticulate systems which are designed to target the compound to blood components or one or more organs.
  • compositions may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use.
  • sterile liquid carrier for example water for injection
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Unit dosage pharmaceutical compositions include those containing a daily dose or daily subdose of the active ingredients, as hereinbefore recited, or an appropriate fraction thereof.
  • compositions of this invention may include other agents conventional in the art having regard to the type of pharmaceutical composition in question, for example, those suitable for oral administration may include such further agents as sweeteners, thickeners and flavoring agents.
  • the compounds of the present invention may be prepared according to the following reactions schemes and examples, or modifications thereof using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are known to those of ordinary skill in the art.
  • R 1 is hydrogen
  • A is 1,2,4-triazole and all other substituents are as hereinbefore defined.
  • A is a 1,2,4-triazole ring comprises the steps of:
  • This general method can readily be carried out by combining a compound of formula (VII) with a compound of formula (VIII) in a suitable solvent, optionally in the presence of an acid, and heating the mixture with a microwave source at 150-200 °C.
  • Typical solvents include but are not limited to 1,4-dioxane, l-methylpyrrolidin-2- one and the like.
  • the acid is typically acetic acid and the like.
  • the solvent is 1,4-dioxane and the acid is acetic acid.
  • the solvent is l-methylpyrrolidin-2-one and the acid is acetic acid.
  • Compound of the formula (VIII) are either commercially available or can be made by methods commonly known to those skilled in the art.
  • Compounds of the general formula (VII) can be made by cyclization of a compound of formula (VI)
  • a compound of formula (VI) in a suitable solvent is treated with a base optionally with heating to 50 to 100 °C.
  • suitable solvents include but are not limited to the lower alcohols such as methanol and ethanol, l-methylpyrrolidin-2-one, N,N-dimethylformamide, tetrahydrofuran, toluene and the like.
  • Bases include by way of example sodium ethoxide, sodium methoxide, sodium tert-butoxide, lithium bis- frimethylsilylamide, sodium hydride and the like.
  • dialkyldiazodicarboxylate is diethyl- or diisopropyldiazodicaboxylate.
  • R 1 is hydrogen
  • A is 1,2,4-oxadiazole and all other substituents are as hereinbefore defined
  • the process for preparing compounds of Formula (I) wherein R 1 is H, A is a 1,3,4-oxadiazole comprises the steps of: a) displacement of the hydroxyl group in an alcohol of formula (IV) with a sulfonylated glycine derivative of formula (IX) to give a compound of formula (X); b) cyclization of a compound of formula (X) to give a compound of formula (XI); c) either- 1) reacting a compound of formula (XI) with a hydrazine to give a hydrazide of formula (XII);
  • compounds of formula (I) wherein R 1 is H, A is a 1,3,4- oxadiazole can be prepared by reacting a compound of formula (XIV) with a dehydrating reagent dehydrating reagent
  • This general method can readily be carried out using common dehydrating agents or conditions well known to one skilled in the art optionally in an inert solvent.
  • Representative conditions are defined as but not limited to (methoxycarbonylsulfamoyl)triethylammonium hydroxide, inner salt (commonly referred to as the Burgess reagent ), friphenylphosphine and an activating agent such as iodine or carbon tetrachloride optionally in the presence of a base such as imidazole or friethylamine, phosphorous oxychloride and the like.
  • reagents can optionally be used in an inert solvent such as chloroform, dichloromethane, 1- methylpyrrolidin-2-one, N,N-dimethylformamide, tetrahydrofuran, toluene and the like.
  • the coupling reagents include but are not limited to l-(3- dimethylaminopropyl)-3 -ethylcarbodiimide hydrochloride, dicyclohexylcarbodiimide, carbonyl di-imidazole and the like.
  • Typical solvents include by way of example dichloromethane, and N,N-dimethylformamide.
  • the coupling of an acid chloride of formula (XIII) to a compound of formula (XII) can be readily carried out by numerous conditions well known to one skilled in the art and prevalent in the literature. Typical conditions may involve an inert solvent such as dichloromethane and the presence of a base such as pyridine or friethylamine or in pyridine neat.
  • Compounds of general formula (XII) can be prepared from a compound of formula (XI). According to this method, the compound of formula (XI) is treated with hydrazine in an inert solvent optionally with heating,
  • an alternative strategy to form a compound of formula XIV involves coupling an acid of formula (XV) with a hydrazide of formula (VIII).
  • the coupling reagents include but are not limited to l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride, dicyclohexylcarbodiimide, carbonyl di-imidazole and the like.
  • Typical solvents include by way of example dichloromethane, and N,N- dimethylformamide.
  • the compound of formula (XV) can be readily prepared by hydrolysis of a compound of formula (XI). Typical conditions for this type of hydrolysis reaction involve treating a compound of formula (XI) with aqueous sodium hydroxide or lithium hydroxide in an inert solvent such as tetrahydrofuran, or methanol or mixtures of methanol, tetrahydrofuran and water.
  • an inert solvent such as tetrahydrofuran, or methanol or mixtures of methanol, tetrahydrofuran and water.
  • R 1 halogen
  • R 1 halogen
  • R 1 is halogen and all other substituents are as hereinbefore defined.
  • the process for preparing compounds of the formula (I) wherein R 1 is halogen involves all the steps outlined for scheme 1 or 2 plus the halogenation of a compound of formula (VII) or (XI ) to give compound of formula (VII- A) or (XI- A) respectively.
  • compounds of formula (VII- A) or (XI- A) wherein R 1 is halogen can be prepared by reacting a compound of formula (VII) or (XI ) with an eletrophilic halogenating reagent in an inert solvent optionally with heating.
  • halogenating reagents include but are not limited to N-bromosuccinimide, bromine, iodine, iodine monochloride, N-chlorosuccinimide, tetraalkylammonium tribromides and the like.
  • Solvents include but are not limited to l-methylpyrrolidin-2- one, N,N-dimethylformamide, tetrahydrofuran, dichloromethane, chloroform, acetic acid and the like.
  • R 1 is hydrogen, halogen, A is 1,3,4-oxadiazole and all other substituents are as hereinbefore defined.
  • the process for preparing compounds of the formula (I) wherein R 1 is H, halogen, A is a 1,3,4-oxadiazole comprises the steps of: a) Methylation of a compound of formula (XI) to provide a compound of formula (XVI); b) Hydrolysis of an ester of formula (XVI) to give an acid of formula
  • compounds of formula (I) wherein R 1 is H, A is a 1,3,4- oxadiazole can be prepared by demthylation of a compound of formula (XIX) with a Lewis acid in an inert solvent.
  • the Lewis acid is frimethylsilyl iodide formed in situ from the addition of sodium iodide and frimethylsilyl chloride.
  • An inert solvent is acetonitrile and the like. Numerous variations of these conditions are well known to those skilled in the art as common deprotection conditions and can be readily found in the literature.
  • the coupling reagents include but are not limited to l-(3- dimethylaminopropyl)-3 -ethylcarbodiimide hydrochloride, dicyclohexylcarbodiimide, carbonyl di-imidazole and the like.
  • Typical solvents include by way of example dichloromethane, and N,N-dimethylformamide.
  • the compound of formula (XVII) can be readily prepared by hydrolysis of a compound of formula (XVI). Typical conditions for this type of hydrolysis reaction involve treating a compound of formula (XVI) with aqueous sodium hydroxide or lithium hydroxide in an inert solvent such as tetrahydrofuran, or methanol or mixtures of methanol, tetrahydrofuran and water.
  • an inert solvent such as tetrahydrofuran, or methanol or mixtures of methanol, tetrahydrofuran and water.
  • methylation is carried out using a methyl halide or sulfate in an inert solvent optionally with a base.
  • methylating reagents include methyl iodide, dimethyl sulfate, methyl triflate, trimethyloxonium tefrafluoroborate, diazomethane, frimethylsilyldiazomethane and the like.
  • bases include potassium carbonate, cesium carbonate, sodium hydroxide, sodium hydride and the like.
  • Inert solvents include but are not limited to acetonifrile, l-methylpyrrolidin-2- one, N,N-dimethylformamide, tetrahydrofuran and the like.
  • R 1 is hydrogen, halogen, A is 1,2,4-triazole and all other substituents are as hereinbefore defined.
  • the process for preparing compounds of the formula (I) wherein R 1 is H, halogen, A is a 1,2,4-oxadiazole comprises the steps of: a) Reacting a compound of formula (VII) with hydroxylamine to form a compound of formula (XX); b) Condensing a compound of formula (XX) with an acid chloride to form a compound of formula (I).
  • 1,2,4-oxadiazole can be prepared by reacting a compound of formula (XX) with an acid chloride or equivalent reagent (XIII) optionally with heating in an inert solvent. In some cases a base may also be required.
  • Compounds of the formula (XX) may be readily prepared by reacting a compound of formula (VII) with hydroxylamine hydrochloride in a solvent such as ethanol and the like. This reaction may optionally be heated to 40-80 °C
  • R 1 is hydrogen, halogen, A is 1,3,4-thiadiazole and all other substituents are as hereinbefore defined.
  • the process for preparing compounds of the formula (I) wherein R 1 is H, halogen, A is a 1,3,4-thiadiazole comprises the steps of: a) Cyclization of a compound of formula (XVIII) to give a thiadiazole of formula (XXI); b) Demethylation of a compound of formula (XXI) to give a compound of formula (I).
  • compounds of formula (I) wherein R 1 is H, halogen, A is a 1,3,4-thiadiazole can be prepared by demethylation of a compound of formula (XXI) with a Lewis acid in an inert solvent.
  • the Lewis acid is frimethylsilyl iodide formed in situ from the addition of sodium iodide and frimethylsilyl chloride.
  • An inert solvent is acetonifrile and the like. Numerous variations of these conditions are well known to those skilled in the art as common deprotection conditions and can be readily found in the literature.
  • This general method can readily be carried out by heating a mixture of a compound of formula (XVIII) and Lawesson's reagent in a solvent such as toluene and the like.
  • R 1 is hydrogen
  • A is 4-pyrimidinyl
  • Q is C 1-3 alkyl, -C(OR 4 )-, or -CF 2 and all other substituents are as hereinbefore defined.
  • M 1 is lithium, or magnesium halide, cerium dihalide.
  • the process for preparing compounds of the formula (I) wherein R 1 is H, halogen, A is a 4-pyrimidine comprises the steps of: a) Reduction of a compound of formula (XVI) to give a compound of formula (XXII); b) Reaction of a compound of formula (XXII) with a compound of formula (XXIII) to give a compound of formula (XXIV); c) Oxidation of a compound of formula (XXIV) to give a compound of formula (XXV); d) Condensation of a compound of formula (XXV) with a compound of formula (XXVI) to give a compound of formula (XVII); e) Demethylation of a compound of formula (XXVII) to give a compound of formula (I).
  • compounds of formula (I) wherein R 1 is H, halogen, A is a 4-pyrimidine can be prepared by demethylation of a compound of formula (XXVII) with a Lewis acid in an inert solvent.
  • the Lewis acid is frimethylsilyl iodide formed in situ from the addition of sodium iodide and frimethylsilyl chloride.
  • An inert solvent is acetonifrile and the like. Numerous variations of these conditions are well known to those skilled in the art as common deprotection conditions and can be readily found in the literature.
  • Typical oxidants well known to one skilled in the art may be employed for this transformation.
  • suitable oxidants may include manganese dioxide, pyridinium chlorochromate and the like.
  • Solvents include but are not limited to chloroform, dichloromethane and the like.
  • Compounds of formula (XXIV) may be prepared by reacting a compound of formula (XXII) with a compound of formula (XXIII) in an inert solvent at or below ambient temperature.
  • this type of reaction may be performed in a solvent such as tetrahydrofuran and the like at -78 °C to room temperature.
  • a solvent such as tetrahydrofuran and the like at -78 °C to room temperature.
  • Compounds of the formula (XXIII) may be prepared according to methods found in the literature or by treating a the corresponging terminal alkyne with a suitable base such as lithium diisopropyl amide or butyllithium and the like.
  • Compounds of the formula (XXII) may be readily prepared by treating a compound of formula with an appropriate reducing agent in an inert solvent, optionally at a low temperature.
  • Reducing agents well known to those skilled in the art may be used.
  • reagents such as diisobutyl aluminum hydride and the like may be used.
  • Solvents include but are not limited to hexanes, tefrahydrofuran, dichloromethane and the like.
  • the reaction may optionally be carried out at temperatures of -78 °C to room temperature.
  • compounds of formula (I) may be converted to other compounds of formula (I) using techniques well known in the art.
  • one method of converting a compound of formula (I) to other compounds of formula (I) involves heating a compound of formula (I- A) wherein R 1 is a halogen with an amine of formula HNR 4 R 5 or heterocycle to form a compound of formula (I-B).
  • compounds of formula (I-A) can be converted to compounds of formula (I-B) by heating with suitably nucleophilic amine either neat or in an inert solvent.
  • inert solvents include but are not limited to the lower alcohols, l-methylpyrrolidin-2-one, N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane and the like.
  • a base such as potassium carbonate can be added
  • Another particularly useful method of converting a compound of formula (I) to other compounds of formula (I) comprises reacting a compound of formula (I-C) with a halogenating reagent to give a compound of formula (I-D).
  • This procedure may be carried out by reacting a compound of formula (I-C) wherein R 1 is H with a halogenating reagent in an inert solvent.
  • a halogenating reagent is well known to those skilled in the art including but are not limited to N- bromosuccinimide, bromine, iodine, iodine monochloride, N-chlorosuccinimide, tetraalkylammonium fribromides and the like.
  • Solvents include but are not limited to l-methylpyrrolidin-2-one, N,N-dimethylformamide, tefrahydrofuran, dichloromethane, chloroform, acetic acid and the like.
  • methyl ether protected precursors to compound of formula (I) are a particularly useful intermediate to convert to other precursors to compounds of formula (I).
  • Several of the above methods described throughout the schemes can be applied to a compound of formula (XLX) and related compounds.
  • one method of converting a compound of formula (XIX) can to other compounds of the formula (XIX) comprises reacting a compound of formula (XIX-A) wherein R 1 is a halogen with an amine of formula H ⁇ R 4 R 5 or heterocycle to form a compound of formula (XIX-B).
  • This procedure may be carried out in an analogous manner to that described above by heating a compound of formula (XIX-A) with a nucleophilic amine either neat or in an inert solvent.
  • Inert solvents include but are not limited to the lower alcohols, l-methylpyrrolidin-2-one, N,N-dimethylformamide, tetrahydrofuran, 1,4- dioxane and the like.
  • a base such as potassium carbonate can be added.
  • a compound of formula (XIX-B) can be converted to a compound of formula (I).
  • Another particularly useful method of converting a compound of formula (XIX) to other compounds of formula (XIX) involves reacting a compound of formula (XIX-A) with an amide, lactam, sulfonamide or sultam using conditions outlined in the literature (Buchwald et. al. J. Am. Chem. Soc. 2002, 124, 7421) involving a copper (I) catalyst, a base, ligand in an inert solvent or (Buchwald et. al. J. Am. Chem. Soc. 2002, 124, 6043) using a palladium catalyst, ligand in an inert solvent.
  • a copper (I) source is copper (I) iodide.
  • a suitable ligand is NN'-dimethylethylenediamine and the like.
  • Preferred bases include but are not limited to potassium carbonate, potassium phosphate, sodium bicarbonate and the like.
  • An inert solvent of particular use is toluene.
  • the copper and ligand are used in similar ratios at 2-10 mol percent. The reaction is typically heated to 70 to 100 °C
  • Analytical thin layer chromatography was used to verify the purity of some intermediates which could not be isolated or which were too unstable for full characterization, and to follow the progress of reactions. Unless otherwise stated, this was done using silica gel (Merck Silica Gel 60 F254). Column or flash chromatography was used for the purification of some compounds. The methods employed used either Merck Silica gel 60 (230-400 mesh), and the stated solvent system under pressure or were automated using ISCO combiflash systems with commericially available pre-packed columns and a gradient elution protocol.
  • Diisopropyl azodicarboxylate (0.96 mL, 4.9 mmol) was added dropwise and the resultant solution was allowed to warm to room temperature. The mixture was stirred for 30 minutes and Celite was added and the solvents removed in vacuo. This material was purified by flash chromatography on silica gel (33% ethyl acetate-hexanes with gradient elution) to provide isopropyl 3-( ⁇ (cyanomethyl)[(4- methylphenyl)sulfonyl] amino ⁇ methyl)pyridine-2-carboxy late (1.3 g, 71%) as a white solid..
  • Example 3 7-f5-Benzyl-4H-1.2.4-triazoI-3-vI)-5-fl.l-dioxido-1.2- thiazinan-2-yl)-l,6-naphthyridin-8-ol.
  • the title compound was prepared in a similar manner to that described in example 1 from of 8-hydroxy-l,6-naphthyridine-7-carbonitrile (48 mg, 0.28 mmol) and 2-(3-Chlorophenyl)acetic hydrazide (257 mg, 1.4 mmol) as a yellow solid (4 mg, 5%) .
  • Example 5 7-r5-(3-MethoxybenzylV4H r -1.2.4-triazol-3-yll-1.6- naphthyridin-8-oI.
  • the title compound was prepared in a similar manner to that described in example 1 from of 8-hydroxy-l,6-naphthyridine-7-carbonifrile (50 mg, 0.29 mmol) and 2-(3-methoxyphenyl)acetic hydrazide (270 mg, 1.5 mmol) as a yellow solid (20 mg, 21%) .
  • Example 6 7-[5-(3.4-Dimethoxybenzyl)-4H-1.2.4-triazol-3-yl1-1.6- naphthyridin-8-ol.
  • Example 9 1 7 5-(4-Fluorobenzyl ⁇ -4iy-1.2.4-triazol-3-yl1-8-hvdroxy- l,6-naphthyridin-5-yllpiperidin-2-one
  • N,8-Dihydroxy[l,6]naphthyridine-7-carboximidamide To a suspension of 8-hydroxy[l,6]naphthyridine-7-carbonifrile (1.0 g, 5.85 mmol) in ethanol (20 mL) was added hydroxylamine hydrochloride (2.0 g, 29.3 mmol) and potassium carbonate (8.1 g, 58.5 mmol). The reaction mixture was refluxed for 1.5 hours. The reaction mixture was cooled and diluted with water (80 mL). The resultant mixture was concentrated in vacuo to remove excess ethanol.
  • reaction mixture was concentrated in vacuo and purifield by medium pressure reverse phase liquid chromatography (5% acetonifrile/95% water with 0.1 % TFA gradient to 100% acetonifrile) to provide 7- (5-benzyl-l,2,4-oxadiazol-3-yl)-l,6-naphthyridin-8-ol (2 mg, 6%) as a yellow solid.
  • Example 12 5-(l.l-Dioxido-1.2-thiazinan-2-yl)-7- f5-f 4-fluorobenzvn-4H- l,2.,4-triazol-3-yll-l, 6-naphthyridin-8-ol.
  • Example 13 7-r5-(4-Chlorobenzviy4H-1.2.4-triazoI-3-yll-5-(l.l-dioxido- 1.2-thiazinan-2-vI)-l,6-naphthyridin-8-ol.
  • the title compound was prepared in a similar manner to that described in example 3 from 5-( 1,1 -dioxido- l,2-thiazinan-2-yl)-8-hydroxy-l,6-naphthyridine-7- carbonitrile (75 mg, 0.24 mmol) and 2-(4-chlorophenyl)acetic hydrazide (137 mg, 0.74 mmol) to give a white solid (49 mg, 43%). !
  • the aqueous layer was then acidified to pH 5 and the solids formed were collected. This material was azeotroped with methanol to provide 5-bromo-7-[5-(4- fluorobenzyl)-4H-l,2,4-triazol-3-yl]-l,6-naphthyridin-8-ol (0.17 g, 42%) as a yellow solid.
  • Example 16 7-r5-(4-Fluorobenzvn-4H r -1.2.4-triazol-3-yll-5-(4- methylpiperazin-l-yl)-l,6-naphthyridin-8-ol.
  • Example 17 7-r5-f4-FIuorobenzyl)-4H-l,2,4-triazol-3-yll-5-morphoIin-4- yl-l,6-naphthyridin-8-ol.
  • Example 18 4- ⁇ 7-r5-(4-Fluorobenzyl>4#-1.2.4-triazol-3-yl1-8-hvdroxy- l,6-naphthyridin-5-vI ⁇ piperazin-2-one.
  • the resultant mixture was cooled to room temperature and Celite was added.
  • the solids were filtered through a pad of Celite and the filtrate was treated with excess disodium EDTA solution and stirred vigorously for 3 hours.
  • the layers were separated and the aqueous layer was extracted twice with dichloromethane and the combined organics were dried over sodium sulfate.
  • the title compound was prepared in a similar manner to example 21 from 5-( 1,1 -dioxido- l,2-thiazinan-2-yl)-8-hydroxy-l,6-naphthyridine-7- carbohydrazide (44 mg, 0.11 mmol) and 2-(4-fluorophenyl)acetyl chloride to provide 5-( 1 , 1 -dioxido- 1 ,2-thiazinan-2-yl)-7-[5-(4-fluorobenzyl)- 1 ,3 ,4-oxadiazol-2-yl]- 1 ,6- naphthyridin-8-ol (7 mg, 15%) as a white solid. !
  • Example 22 7-f5-Benzyl-lH-1.2.4-triazol-3-ylV5-ri- pyrrolidinvD [1,61 naphthyridin-8-ol.
  • the reaction mixture was heated at 80 °C for 2 hours.
  • the reaction mixture was cooled and diluted with ethyl acetate.
  • the organic layer was washed with water and brine, then dried over sodium sulfate. Filtration and concentration, followed by flash chromatography provided 8-(benzyloxy)-5-(l-py ⁇ Olidinyl)[l,6]naphthyridine-7-carbonitrile (34 mg, 63 %) as a white solid.
  • the combined filtrate was concentrated and purified by preparative ⁇ PLC
  • the isolated material was dissolved in 1 N sodium hydroxide solution and washed with dichloromethane.
  • the basic layer was acidified with 1 N hydrochloric acid solution, then extracted with ethyl acetate.
  • the concentrated organic layer was dissolved in dichloromethane and 1 N hydrogen chloride was added.
  • Precipitated solid was separated from mother liquor. Solid was partitioned between ethyl acetate and saturated sodium bicarbonate solution. Organic layer was separated and washed with water and brine, then dried over sodium sulfate.
  • a stock solution of catalyst was prepared by adding N, N'- dimethylene diamine (93 ⁇ L, 0.866 mmol) to a stirring suspension of copper (I) iodide (165 mg, 0.866 mmol) in toluene (15 mL). To the original solution was added 150 ⁇ L stock solution and the reaction mixture was stirred at 90 °C for 30 minutes. Five addititional aliquots of 150 ⁇ L stock solution were added every 30 minutes. The reaction mixture was cooled and diluted with ethyl acetate. The resultant mixture was washed with water and brine, then dried over sodium sulfate.
  • NN-dimethylformamide (15 mL) was added cesium carbonate (2.32 g, 7.14 mmol). The resultant mixture was stirred for 30 minutes upon which time a bright yellow paste was formed. To this stirring paste was added iodomethane (666 ⁇ L, 10.7 mmol) and the resulting mixture was stirred 16 hours at room temperature. The reaction was quenched with ice water, then diluted with ethyl acetate. The organic layer was washed with water and brine, then dried over sodium sulfate.
  • reaction mixture was then partitioned between water and dichloromethane (a large excess of dichloromethane was needed to solubilize product).
  • the organic layer was washed with water and brine, then dried over sodium sulfate. Filtration and concentration, followed by flash chromatography (0% to 10 % methanol in dichloromethane) to provide 5-bromo-8-methoxy-N-(phenylacetyl)[l,6]naphthyridine-7-carbohydrazide (328 mg, 79 %) as a white solid.
  • Example 38 5-f 1.l-Dioxido-1.2-thiazinan-2-yl -7-r5-fpyridin-4-ylmethvn- 4ff-1.2.4-triazol-3-vIl-1.6-naphthyridin-8-ol.
  • Example 40 7-r5-f3.5-Difluorobenzyl -4H-1.2.4-triazol-3-yll-5-(i ⁇ - dioxido-l,2-thiazinan-2-yl)-l,6-naphthyridin-8-ol.
  • Example 42 5-(l,l-Dioxido-1.2-thiazinan-2-yl)-7-r5-f3-fluorobenzyl)-4H- l,2,4-triazol-3-yll-l,6-naphthyridin-8-ol.
  • Example 50 7-r5-f4-Fluorobenzvn-4ff-1.2.4-triazol-3-yl1-5-(4- hvdroxypiperidin-l-yl)-l,6-naphthyridin-8-ol.
  • Example 52 7-r5-f4-Flttorobenzvn-4H-1.2.4-triazoI-3-vn-5- ⁇ 4-r2-f2- hvdroxyethoxy)ethyllpiperazin-l-yl ,6-naphthyridin-8-oI.
  • Example 54 7-[5-(4-Fluorobenzyl)-4.ff-l,2,4-triazol-3-yll-5-(4-pyrazin-2- ylpiperazin-l-yl)-l,6-naphthyridin-8-ol.
  • Example 55 7-r5-f4-FluorobenzylV4fl-1.2.4-triazoI-3-yll-5-r4-(2- morpholm-4-yl-2-oxoethyl)piperazin-l-vn-l,6-naphthyridin-8-ol.
  • Examples 57 - 184 may be prepared by methods described above.
  • Antiviral HIV activity and compound-induced cytotoxicity were measured in parallel by means of a propidium iodide based procedure in the human T-cell lymphofropic virus transformed cell line MT4. Aliquots of the test compounds were serially diluted in medium (RPMI 1640, 10% fetal calf serum (FCS), and gentamycin) in 96-well plates (Costar 3598) using a Cetus Pro/Pette. Exponentially growing MT4 cells were harvested and cenfrifuged at 1000 rpm for 10 min in a Jouan centrifuge (model CR 4 12).
  • Cell pellets were resuspended in fresh medium (RPMI 1640, 20% FCS, 20%) IL-2, and gentamycin) to a density of 5 x 105 cells/ml.
  • Cell aliquots were infected by the addition of HIV- 1 (strain IIIB) diluted to give a viral multiplicity of infection of 100 x TCID50.
  • HIV- 1 strain IIIB
  • a similar cell aliquot was diluted with medium to provide a mock-infected control.
  • Cell infection was allowed to proceed for 1 hr at 37°C in a tissue culture incubator with humidified 5% C0 2 atmosphere.
  • the virus/cell suspensions were diluted 6-fold with fresh medium, and 125 ⁇ l of the cell suspension was added to each well of the plate containing pre-diluted compound. Plates were then placed in a tissue culture incubator with humidified 5% CO 2 for 5 days. At the end of the incubation period, cell number and hence HIV- induced cytopathy was estimated by either (A) propidium iodide staining, or by an (B) MTS tetrazolium staining method (ref. 5).
  • the assay makes use of a propidium iodide dye to estimate the DNA content of each well.
  • 20 ⁇ l CellTiter 96 AQ One Solution reagent (Promega #G3582) was added to each well.
  • absobance was read at 492 nM using a Tecan Sunrise 96-well plate reader.
  • IC50 The antiviral effect of a test compound is reported as an IC50, i.e. the inhibitory concenfration that would produce a 50% decrease in the HIV-induced cytopathic effect. This effect is measured by the amount of test compound required to restore 50% of the cell growth of HIV-infected MT4 cells, compared to uninfected MT4 cell controls. IC 50 was calculated by RoboSage, Automated Curve Fitting Program, version 5.00, 10-Jul-1995.
  • results for each assay plate, the results (relative fluorescence units, rfU, or OD values) of wells containing uninfected cells or infected cells with no compound were averaged, respectively.
  • results from wells containing various compound concentrations and uninfected cells were compared to the average of uninfected cells without compound treatment. Percent of cells remaining is determined by the following formula:
  • Percent of cells remaining (compound-treated uninfected cells, rfU, or OD values / unfreated uninfected cells) x 100.
  • a level of percent of cells remaining of 79% or less indicates a significant level of direct compound-induced cytotoxicity for the compound at that concenfration.
  • the results from the compound-treated infected wells at this concenfration are not included in the calculation of IC 50 .
  • results from wells containing various compound concentrations and infected cells are compared to the average of uninfected and infected cells without compound treatment. Percent inhibition of vims is determined by the following formula:
  • Percent inhibition of vims (l-((ave. imfreated uninfected cells - treated infected cells) / (ave. unfreated uninfected cells - ave. unfreated infected cells)))x 100 References:

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Abstract

L'invention concerne des composés qui sont des inhibiteurs de l'intégrase du VIH. Ces composés sont par conséquent utiles pour l'inhibition de la réplication du VIH, pour la prévention et/ou pour le traitement d'une infection par VIH, et pour le traitement du SIDA et/ou de l'ARC.
PCT/US2004/014814 2003-05-13 2004-05-12 Inihbiteurs de l'integrase de la naphtyridine WO2004101512A2 (fr)

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US10/556,311 US7812016B2 (en) 2003-05-13 2004-05-12 Naphthyridine integrase inhibitors
EP04751959A EP1622615A4 (fr) 2003-05-13 2004-05-12 Inihbiteurs de l'integrase de la naphtyridine
JP2006532973A JP2006528694A (ja) 2003-05-13 2004-05-12 ナフチリジンインテグラーゼインヒビター
US12/871,230 US20110003794A1 (en) 2003-05-13 2010-08-30 Naphthyridine Integrase Inhibitors

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WO2007079260A1 (fr) 2005-12-30 2007-07-12 Gilead Sciences, Inc. Procedes pour l'amelioration de la pharmacocinetique d'inhibiteurs de l'integrase vih
WO2007092802A1 (fr) * 2006-02-09 2007-08-16 Boehringer Ingelheim International Gmbh Méthode pour traiter une infection au vih par co-administration de tipranavir et de gs 9137
WO2010015520A1 (fr) * 2008-08-05 2010-02-11 Boehringer Ingelheim International Gmbh Naphtyridines substituées et leur utilisation en tant que médicaments
DE102008059133A1 (de) 2008-11-26 2010-05-27 Merck Patent Gmbh Difluorphenyl-diacylhydrazid-derivate
WO2011120153A1 (fr) 2010-04-01 2011-10-06 Critical Outcome Technologies Inc. Composés et méthodes pour le traitement du vih
US8110705B2 (en) 2007-05-22 2012-02-07 Wyeth Llc Processes for making hydrazides
US8129385B2 (en) 2005-04-28 2012-03-06 Shionogi & Co., Ltd. Substituted 5-hydroxy-3,4,6,9,9a, 10-hexanhydro-2h-1-oxa04a,8a-diaza-anthracene-6,10-dioness
US8143405B2 (en) * 2006-09-21 2012-03-27 Merck, Sharp & Dohme Corp Piperidine and pyrrolidine beta-secretase inhibitors for the treatment of alzheimer's disease
JP7566753B2 (ja) 2019-01-03 2024-10-15 ユニバーシティ オブ ピッツバーグ －オブ ザ コモンウェルス システム オブ ハイヤー エデュケイション 転写因子ｅｂポリペプチドレベルを増加させるための方法および材料

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US9051337B2 (en) 2005-04-28 2015-06-09 Shionogi & Co., Ltd. Substituted 10-hydroxy-9,11-dioxo-2,3,4a,5,9,11,13,13a-octahydro-1h-pyrido[1,2-a]pyrrolo[1′,2′:3,4]imidazo[1,2-d]pyrazine-8-carboxamides
US9273065B2 (en) 2005-04-28 2016-03-01 Shionogi & Co., Ltd. Substituted pyrido[1',2':4,5]pyrazino[1,2-a]pyrimidines as HIV integrase inhibitors
US8410103B2 (en) 2005-04-28 2013-04-02 Shionogi & Co., Ltd. (3S,11aR)-N-[2,4-difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide useful as anti-HIV agent
US8778943B2 (en) 2005-04-28 2014-07-15 Shionogi & Co., Ltd. Substituted 10-hydroxy-9,11-dioxo-2,3,4a,5,9,11,13,13a-octahydro-1h-pyrido[1,2-α]pyrrolo[1′,2′:3,4]imidazo[1,2-d]pyrazine-8-carboxamides
US11267823B2 (en) 2005-04-28 2022-03-08 Shionogi & Co., Ltd. Substituted 1,2,3,3a,4,5,7,9,13,13a-decahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrrolo[1,2-c]pyrimidines having HIV integrase inhibitory activity
US8129385B2 (en) 2005-04-28 2012-03-06 Shionogi & Co., Ltd. Substituted 5-hydroxy-3,4,6,9,9a, 10-hexanhydro-2h-1-oxa04a,8a-diaza-anthracene-6,10-dioness
US10927129B2 (en) 2005-04-28 2021-02-23 Shinogi & Co., Ltd. N-[(2,4-difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3] oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide having HIV integrase inhibitory activity
EA018544B1 (ru) * 2005-12-30 2013-08-30 Джилид Сайэнс, Инк. Способ лечения ретровирусной инфекции
EP2308490A1 (fr) * 2005-12-30 2011-04-13 Gilead Sciences, Inc. Procedes pour l'amelioration de la pharmacocinetique d'inhibiteurs de l'integrase vih
CN104069108A (zh) * 2005-12-30 2014-10-01 吉里德科学公司 改善hiv整合酶抑制剂的药物动力学的方法
AU2006332664B2 (en) * 2005-12-30 2013-03-14 Gilead Sciences, Inc. Methods for improving the pharmacokinetics of HIV integrase inhibitors
JP2009525265A (ja) * 2005-12-30 2009-07-09 ギリアド サイエンシズ， インコーポレイテッド Ｈｉｖインテグラーゼ阻害剤の薬物動態の改善方法
WO2007079260A1 (fr) 2005-12-30 2007-07-12 Gilead Sciences, Inc. Procedes pour l'amelioration de la pharmacocinetique d'inhibiteurs de l'integrase vih
AP2702A (en) * 2005-12-30 2013-07-23 Gilead Sciences Inc Methods for improving the pharmacokinetics of HIV integrase inhibitors
WO2007092802A1 (fr) * 2006-02-09 2007-08-16 Boehringer Ingelheim International Gmbh Méthode pour traiter une infection au vih par co-administration de tipranavir et de gs 9137
US8143405B2 (en) * 2006-09-21 2012-03-27 Merck, Sharp & Dohme Corp Piperidine and pyrrolidine beta-secretase inhibitors for the treatment of alzheimer's disease
US9227924B2 (en) 2007-05-22 2016-01-05 Wyeth Llc Processes for making hydrazides
US8853451B2 (en) 2007-05-22 2014-10-07 Wyeth Llc Processes for making hydrazides
US9738602B2 (en) 2007-05-22 2017-08-22 Wyeth Llc Processes for making hydrazides
US8383857B2 (en) 2007-05-22 2013-02-26 Wyeth Llc Processes for making hydrazides
US8110705B2 (en) 2007-05-22 2012-02-07 Wyeth Llc Processes for making hydrazides
EP2465541B1 (fr) * 2007-05-22 2018-07-18 Wyeth LLC Procédés améliorés de fabrication d'hydrazides
WO2010015520A1 (fr) * 2008-08-05 2010-02-11 Boehringer Ingelheim International Gmbh Naphtyridines substituées et leur utilisation en tant que médicaments
DE102008059133A1 (de) 2008-11-26 2010-05-27 Merck Patent Gmbh Difluorphenyl-diacylhydrazid-derivate
EP3235818A2 (fr) 2010-04-01 2017-10-25 Critical Outcome Technologies, Inc. Composés pour le traitement du vih
WO2011120153A1 (fr) 2010-04-01 2011-10-06 Critical Outcome Technologies Inc. Composés et méthodes pour le traitement du vih
JP7566753B2 (ja) 2019-01-03 2024-10-15 ユニバーシティ オブ ピッツバーグ －オブ ザ コモンウェルス システム オブ ハイヤー エデュケイション 転写因子ｅｂポリペプチドレベルを増加させるための方法および材料

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